Method for the generation of chemical libraries

Abstract

A method for the generation of oligomers or a mixture of oligomers to form a chemical library by amide-forming oligomerization comprises the steps of 1) reacting a mixture of at initiator (I) with monomer (M) to form a dimer of the initiator (I) and the monomer (M) or a pre-oligomer with an initiator (I) attached to a chain of more than one monomer (M) or a mixture thereof by amide-bond formation; 2) optionally adding at least one terminator (T) for the formation of a linear oligomer or a mixture of linear oligomers by amide-bond formation; or, for the formation of a cyclic oligomer or a mixture of cyclic oligomers by amide-bond formation, changing the reaction conditions relative to step 1) so as to form a linking covalent bond between the at least one initiator (I).

1 . A method for the generation of oligomers or a mixture of oligomers to form a chemical library by amide-forming oligomerization comprising the steps of:
 1) reacting a mixture of at least one initiator with at least one monomer to form a dimer of the initiator and the monomer or
 to form a pre-oligomer with an initiator attached to a chain of more than one monomer, or a mixture thereof by amide-bond formation; 
   2) adding at least one terminator for the formation of a linear oligomer or a mixture of linear oligomers by amide-bond formation;
 or, for the formation of a cyclic oligomer or a mixture of cyclic oligomers by amide-bond formation, changing the reaction conditions relative to step 1) so as to form a linking covalent bond between the at least one initiator and a monomer of the dimer or pre-oligomer formed in step 1), 
   with the proviso that
 step 2) can be omitted so that the dimer of the initiator and the monomer or the pre-oligomer with an initiator attached to a chain of more than one monomer, or a mixture thereof is formed as the linear oligomer or mixture of linear oligomers by amide-bond formation; 
   wherein the initiator is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         with, for the formation of a linear oligomer or a mixture of linear oligomers by amide-bond formation, 
         R being selected from the group consisting of: substituted or unsubstituted alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, heteroalkylaryl, alkenyl, heteroalkenyl, alkinyl, heteroalkinyl, —C(NH 2 )R I , —C(NH 2 ){R I —CO—C(NH 2 )} n R I  with n=1, 2 and R I  being H or an amino-acid side chain, fluorescent dye, nucleic acid or derivative thereof, peptide nucleic acid, FLAG octapeptide (DYKDDDDK), biotin or affinity tag; 
         or with, for the formation of a cyclic oligomer or a mixture of cyclic oligomers by amide-bond formation, 
         R being selected from the group consisting of: —{(CH 2 )} n R c , —{(CHCH 3 )} n R c , {(CH(1,1-dimethylethyl))} n R c , —{(CH(benzyl))} n R c , in each case with n=1,2 and R c  being a linker structure allowing to form a linking covalent amide bond to the respective terminal monomer of the dimer or oligomer formed in step 1); 
         and in both cases with 
         X +  being a counterion, selected from the group consisting of: K + , Cs + , Li + , Na + , R 4 N + , R 4 P +  or R 3 S +  with R being an organic substituent or H; 
         X, Y, Z, being, independently from each other, selected from the group consisting of: F, OR, N + R 3 , N + R 2 OR, N + R 2 SR, and N + R 2 NR 2 , and including the situation of forming a cyclic or a bicyclic structure; wherein R is an organic substituent or H; 
         or covalent dimers or trimers thereof with R in this case being a common linker element; 
         wherein the monomer is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         with 
         X being selected from the group consisting of: halogen, —OH, —COOH, —NH 2 , —O-Alkyl, —O-Aryl, —O—CO-Alkyl, —O—CO-Aryl, —SH, S-Alkyl, —S-Aryl, N-Acyl, —NH-Alkyl, —NH-Aryl, —N(Alkyl) 2 , —N(Aryl) 2 , —N(Alkyl)(Aryl), —CO—NH-Alkyl, —CO—NH-Aryl, —CO—N(Alkyl) 2 , —CO—N(Aryl) 2 , —CO—N(Alkyl)(Aryl), —CN, —NO 2 , —N 3 , —S(O)Aryl, —S(O) 2  Aryl; 
         Y being selected from the group consisting of: —PO 3 H, —COOH, —BF 3   − X + , —BXYZ, wherein X + , X, Y, Z are defined as given above in the context of the initiator, 
         Z being selected from the group consisting of: —PO 3 H, —COOH, —BF 3   − X + , —BXYZ, wherein X + , X, Y, Z are defined as given above in the context of the initiator, as well as derivatives thereof which upon collapse of X and Z upon cleavage of the NO bond lead to Y; 
         R being selected from the group consisting of: O, S, NR 1 , Si, CHR 1 R 2 ; 
         R 1 -R 6  being, independently from each other, selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted alkyl, heteroalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylaryl, heteroalkylaryl, alkenyl, heteroalkenyl, alkinyl, heteroalkinyl, as well as cyclic forms linking these among each other; 
         Q being selected from the group consisting of: O, S, Si, NR 1 , where R 1  is an organic substituent or H; 
         and wherein the terminator, if used, is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         with 
         R being selected from the group consisting of: CH 2 , (CH 2 ) 2 , CHR T , CH 2 CHR T , (CH 2 ) 3 , (CH 2 ) 2 CHR T , CH 2 CHR T CH 2 , (CH 2 ) 4 , wherein R T  is selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted alkyl, heteroalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylaryl, heteroalkylaryl, alkenyl, heteroalkenyl, alkinyl, heteroalkinyl; 
         R 1  being selected from the group consisting of: substituted or unsubstituted alkyl, heteroalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylaryl, heteroalkylaryl, alkenyl, heteroalkenyl, alkinyl, heteroalkinyl, ester, carbamate, sulfonate, sulfinate, phosphate, silyl; 
         R 7 -R 9  being, independently from each other, selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted alkyl, heteroalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylaryl, heteroalkylaryl, alkenyl, heteroalkenyl, alkinyl, heteroalkinyl, ester, carbamate, sulfonate, sulfinate, phosphate, silyl, as well as cyclic forms linking these among each other and carbonyl, imidate, thiomidate 
         or covalent dimers or trimers thereof with R 1  and/or at least one of R 7  or R 8  in this case being a common linker element. 
       
     
     
         2 . The method according to  claim 1 , wherein the generation of oligomers or a mixture of oligomers is carried out using the steps of
 1) reacting a mixture of at least one initiator with at least one monomer to form a dimer of the initiator and the monomer or
 to form a pre-oligomer with an initiator attached to a chain of more than one monomer, or a mixture thereof by amide-bond formation; 
   2) adding at least one terminator for the formation of a linear oligomer or a mixture of linear oligomers by amide-bond formation;
 or, for the formation of a cyclic oligomer or a mixture of cyclic oligomers by amide-bond formation, changing the reaction conditions relative to step 1) so as to form a linking covalent bond between the at least one initiator and the respective terminal monomer of the dimer or pre-oligomer formed in step 1). 
   
     
     
         3 . The method according to  claim 1 , wherein one single initiator is used in step 1) and, in case of the formation of a linear oligomer or a mixture of linear oligomers by amide-bond formation, one single terminator is used in step 2). 
     
     
         4 . Method according to  claim 1 , wherein the initiator for the formation of a linear oligomer or a mixture of linear oligomers by amide-bond formation is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         with Me=—CH 3 . 
       
     
     
         5 . The method according to  claim 1 , wherein the initiator for the formation of a cyclic oligomer or a mixture of cyclic oligomers by amide-bond formation is selected in that the linker structure is selected from the group consisting of: a chain of one or two elements selected from the group of: amino acid, CO((CH 2 ) 2 NH, and this chain terminated by a group selected from: 
       
         
           
           
               
               
           
         
         with Bz=benzyl; Boc=tert-butyloxycarbonyl. 
       
     
     
         6 . The method according to  claim 1 , wherein the initiator for the formation of a cyclic oligomer or a mixture of cyclic oligomers by amide-bond formation is given by a structure comprising at one initiator moiety selected from the group consisting of: 
       
         
           
           
               
               
           
         
         with 
         R being a linker element 
         X +  being a counter-ion, selected from the group consisting of: K + , Cs + , Li + , Na + , R 4 N + , R 4 P +  or R 3 S +  with R being an organic substituent or H; 
         X, Y, Z, being, independently from each other, selected from the group consisting of: F, OR, N + R 3 , N + R 2 OR, N + R 2 SR, and N + R 2 NR 2 , and including the situation of forming a cyclic or a bicyclic structure; wherein R is an organic substituent or H; 
         and at least one terminator moiety selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         with 
         R being selected from the group consisting of: CH 2 , (CH 2 ) 2 , CHR T , CH 2 CHR T , (CH 2 ) 3 , (CH 2 ) 2 CHR T , CH 2 CHR T CH 2 , (CH 2 ) 4 , wherein R T  is selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted alkyl, heteroalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylaryl, heteroalkylaryl, alkenyl, heteroalkenyl, alkinyl, heteroalkinyl; 
         R 1  being a linker element; 
         R 7 -R 9  being, independently from each other, selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted alkyl, heteroalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylaryl, heteroalkylaryl, alkenyl, heteroalkenyl, alkinyl, heteroalkinyl, ester, carbamate, sulfonate, sulfinate, phosphate, silyl, as well as cyclic forms linking these among each other and carbonyl, imidate, thiomidate, with the proviso that at least one of R 7  or R 8  is a linker element, 
         linked by a common linker element given by R in the initiator moiety and by R 1  or R 7  or 
         R 8  in the terminator moiety. 
       
     
     
         7 . The method according to  claim 1 , wherein the monomer is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         with Me==—CH 3 ,  t Bu=1,1-dimethylethyl, Cbz=benzyloxycarbonyl, iPr=isopropyl, Ph=phenyl. 
       
     
     
         8 . The method according to  claim 1 , wherein the terminator is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         with 
         R 1  being selected from the group consisting of: substituted or unsubstituted alkyl, heteroalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylaryl, heteroalkylaryl, alkenyl, heteroalkenyl, alkinyl, heteroalkinyl, ester, carbamate, sulfonate, sulfinate, phosphate, silyl; 
         Me=—CH 3 , Et=ethyl; Ph=phenyl. 
       
     
     
         9 . The method according to  claim 1 , wherein step 1) and/or 2) are carried out, apart from solvent(s), without any added further chemical reagents or catalysts; 
     
     
         10 . The method according to  claim 1 , wherein in step 1) and/or in step 2) organic solvents, water, aqueous buffer or combinations thereof are used. 
     
     
         11 . The method according to  claim 1 , wherein in step 1) more than 1, monomer is used, and/or wherein in step 1) the reaction is carried over to lead to oligomers with at least 2 interlinked monomers. 
     
     
         12 . The method according to  claim 1 , wherein in step 1) the reaction conditions are selected so as to lead, between different batches, to targeted different distributions of different oligomers in the mixture. 
     
     
         13 . The method according to  claim 1 , wherein in step 1) one single initiator, one single monomer and, in case of the generation of linear oligomers, in step 2) one single terminator is used, and wherein the reaction conditions in step 1) and/or step 2) are adapted such as to form a specific trimer structure. 
     
     
         14 . The method of identification of biologically and/or chemically active systems from a chemical library based on at least one mixture of oligomers made using a method for the generation of oligomers or a mixture of oligomers according to  claim 1 , wherein the mixtures of oligomers are screened for activity prior to purification or separation of the compounds from the mixture. 
     
     
         15 . The method according to  claim 14 ,
 using a number of specifically differing mixtures wherein in step 1) and/or in step 2) organic solvents, water, aqueous buffer or combinations thereof are used,   checking these mixtures for biological and/or chemical activity,   inferring from activity patterns initiators and/or monomers and/or terminators inducing activity,   preparing further mixtures according to the method for the generation of oligomers or a mixture of oligomers based on the identified active initiators and/or monomers and/or terminators only, thereby successively reducing the number of possible active oligomers.   
     
     
         16 . The method according to  claim 14 ,
 using a number of specifically differing mixtures wherein in step 1) more than 1, monomer is used, and/or wherein in step 1) the reaction is carried over to lead to oligomers with at least 2 interlinked monomers,   checking these mixtures for biological and/or chemical activity,   inferring from activity patterns initiators and/or monomers and/or terminators inducing activity,   preparing further mixtures according to the method for the generation of oligomers or a mixture of oligomers based on the identified active initiators and/or monomers and/or terminators only, thereby successively reducing the number of possible active oligomers.   
     
     
         17 . The method according to  claim 1 , wherein the initiator for the formation of a cyclic oligomer or a mixture of cyclic oligomers by amide-bond formation is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is a linker element; 
         R q  is a structural element complementing to a 4, 5, 6, or 7 membered ring; 
         R t  is a structural element complementing to a 4, 5, 6, or 7 membered ring; 
         R 7 -R 9  being, independently from each other, selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted alkyl, heteroalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylaryl, heteroalkylaryl, alkenyl, heteroalkenyl, alkinyl, heteroalkinyl, as well as cyclic forms linking these among each other and carbonyl, imidate, thiomidate, 
         R being selected from the group consisting of: O, S, NR 1 , SiR 1 R 2 , CR 1 R 2 ; wherein R 1  and R 2  are, independently from each other, selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted alkyl, heteroalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylaryl, heteroalkylaryl, alkenyl, heteroalkenyl, alkinyl, heteroalkinyl, 
         Y being selected from the group consisting of: —PO 3 H, —COOH, —BF 3   − X + , —BXYZ, wherein X + , X, Y, Z are defined as given above in the context of the initiator. 
       
     
     
         18 . The method according to  claim 1 , wherein the initiator for the formation of a cyclic oligomer or a mixture of cyclic oligomers by amide-bond formation is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         with boc=tert-butyloxycarbonyl, Ph=phenyl, Fmoc=fluorenylmethyleneoxycarbonyl, Me=—CH 3 , Bz=benzyl. 
       
     
     
         19 . The method according to  claim 1 , wherein in step 1) 2-6 different monomers are used, and/or wherein in step 1) the reaction is carried over to lead to oligomers with in the range of 2-10 interlinked monomers. 
     
     
         20 . Method according to  claim 1 , wherein in step 1) 2-4 different monomers are used, and/or wherein in step 1) the reaction is carried over to lead to oligomers with in the range of 2-6 interlinked monomers. 
     
     
         21 . The method according to  claim 1 , wherein in step 1) the reaction conditions selected from at least one of temperature, pressure, reactant concentrations, reactant addition order, reactant addition time, reactant chirality are selected so as to lead, between different batches, to targeted different distributions of different oligomers in the mixture. 
     
     
         22 . The method according to  claim 1 , wherein the initiator for the formation of a cyclic oligomer or a mixture of cyclic oligomers by amide-bond formation is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is a linker element; 
         R q  is a structural element complementing to a 4, 5, 6, or 7 membered ring, selected from the group consisting of: —C—, —CH 2 —C—, —CHR T —C—, —(CH 2 ) 2 —C—, —(CHR T ) 2 —C—, —(CH 2 )—C—(CH 2 )—, —(CHR T )—C—(CH 2 )—, —(CHR T )—C—(CHR T )—, —(CH 2 ) 3 —C, wherein R T  is selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted alkyl, heteroalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylaryl, heteroalkylaryl, alkenyl, heteroalkenyl, alkinyl, heteroalkinyl; 
         R t  is a structural element complementing to a 4, 5, 6, or 7 membered ring, selected from the group consisting of: —CR U —, —CH 2 —CR U —, —CHR T —CR U -, —(CH 2 ) 2 —CR U —, —(CHR T ) 2 —CR U —, —(CH 2 )—CR U —(CH 2 )—, —(CHR T )—CR U —(CH 2 )—, —(CHR T )—CR U —(CHR T )—, —(CH 2 ) 3 —CR U , wherein R T  is selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted alkyl, heteroalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylaryl, heteroalkylaryl, alkenyl, heteroalkenyl, alkinyl, heteroalkinyl, and wherein R U  is selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted alkyl, heteroalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylaryl, heteroalkylaryl, alkenyl, heteroalkenyl, alkinyl, heteroalkinyl; 
         R 7 —R 9  being, independently from each other, selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted alkyl, heteroalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylaryl, heteroalkylaryl, alkenyl, heteroalkenyl, alkinyl, heteroalkinyl, as well as cyclic forms linking these among each other and carbonyl, imidate, thiomidate, 
         R being selected from the group consisting of: O, S, NR 1 , SiR 1 R 2 , CR 1 R 2 ; wherein R 1  and R 2  are, independently from each other, selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted alkyl, heteroalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylaryl, heteroalkylaryl, alkenyl, heteroalkenyl, alkinyl, heteroalkinyl, 
         Y being selected from the group consisting of: —PO 3 H, —COOH, —BF 3   − X + , —BXYZ, wherein X + , X, Y, Z are defined as given above in the context of the initiator.